Towards Personalised Therapeutics for Epidermal Differentiation Disorders: Integrating Host Genetics,...

Epidermal differentiation disorders (EDDs), are a rare, heterogeneous grouping of monogenic disorders. EDDs, comprising the previously termed congenital ichthyosis, are characterised by epidermal barrier dysfunction, cutaneous inflammation, and associated morbidity. Immunomodulatory therapies, particularly repurposed biologics, are an emerging approach for management. However, clinical implementation has been impeded by a variable and unpredictable response rate, reflecting the genetic and immunological heterogeneity of EDD as well as raising questions over other contributory pathogenic mechanisms. Patient genotyping and immune profiling have revealed a shared immune polarisation across EDD subtypes, predominantly Th17, with some subtypes demonstrating a mixed immuno-endotype with contribution from Th2 or lL-36 mediated signalling. This improved immunological understanding has informed the repurposing of established biologics targeting IL-4R, IL-17, IL-12/23, alongside emerging interest in JAK inhibitors. Metagenomic microbiome profiling has revealed a homeostatic disruption across EDD subtypes with depleted commensal organisms, including Cutibacterium acnes and Malassezia species, and enrichment of pathobiont Staphylococcus and Corynebacterium species. Patients may be further stratified into dysbiotic groupings, with pathogenic variant and phenotypic severity influencing microbial composition. Ecological dysbiosis may contribute to immune polarisation through an "outside-inside-outside" model of host-microbe interactions, potentially underlying the variable response rates to repurposed biologics. In this review, we propose a "host genome and microbiome" framework for personalised EDD clinical management, integrating the EDD genotype and immuno-endotype ("Host genome"), and cutaneous microbiome as candidate simultaneous stratifiable elements. Genomic diagnosis, spurred by recent EDD reclassification, provides mechanistic context. Immuno-endotyping may enable a rational biologic selection but requires prospective validation. Microbiome profiling may guide emerging therapeutics or serve as a biomarker. We propose that a route to therapeutic restoration in EDD may require simultaneous targeting of the host-microbe axis. Delineation of the complex interplay between host genetics, immuno-endotypes, epidermal barrier dysfunction, and skin microbiome is a key priority for future research to bring this approach to the clinic.